2 & 3D Imaging of Contrast Agents in Animal Models

近红外（NIR）光学成像技术利用固有吸收（mua）和散射（mus’）对人体乳房深处的小异质性进行敏感定位。为了进一步提高光学方法检测癌症的灵敏度和特异性（S/S），我们建议将我们在这一竞争性更新应用中的活动重新聚焦于动物模型中癌症的外在对比。建议的工作将首先确定外源性试剂的优点值M，并使用荧光和吸光度检测动物肿瘤中非常小（20摩尔）量的外源性探针，用近红外造影剂量化M的增加。这些研究需要几种仪器方案，包括：1)提出了一种改进的相控阵系统，该系统将吲哚青绿（ICG）定位到0.2 mm和9L胶质瘤20p摩尔的ICG，用于检测包括前列腺癌和人类乳腺癌在内的动物肿瘤，其中S/S可以在早期小肿瘤中进行评估。将采用另外两种适合动物模型的仪器。2) 1毫米分辨率的飞行点扫描仪，用于浅表肿瘤（仅限小鼠），适用于近红外荧光信号成像。3)需要快速冷冻肿瘤的分辨率小于50微米的三维成像仪将用于在所有非人类肿瘤中定位造影剂。后一种系统对于相控阵系统的关键评估至关重要。将采用上述检测方法在动物模型中比较基于ICG并包含分子信标的7种近红外造影剂。将使用基于肿瘤/组织造影剂(C)、保留时间(R)（min）和荧光量子产率(Q)的优点图(M)进行定量比较。M是根据线性模型（即这三个量的乘积）计算的。因此，对目前可用的造影剂进行密集的、雄心勃勃的定量评估，将提供动物模型数据库转移到人类乳腺肿瘤，使用FDA批准的ICG（以及后来的其他方法）和相控阵定位，在“从实验室到床边”的研究中与钆螯合物肿瘤MRI图像共同注册（NIH Workshop, September 14-17, 2000）。

Near Infrared (NIR) optical imaging technologies provide sensitive localization of small heterogeneities deep within the human breast using intrinsic absorption (mua) and scattering (mus'). In order to achieve a further enhancement of the sensitivity and specificity (S/S) of cancer detection by the optical method, we propose to refocus our activity in this competitive renewal application towards extrinsic contrast in cancers in animal models. The proposed work will first determine the Figure of Merit, M, of the extrinsic agents and to quantify the increase in M with NIR contrast agents using both fluorescence and absorbance detection of the very small (20 pmole) amounts of extrinsic probes in animal tumors. Several instrumentation schemes are required for these studies and include: 1) An improved phased array system with localization of indocyanine green (ICG) demonstrated in model systems to 0.2 mm and 9L glioma 20 p moles of ICG is proposed for animal tumors including prostate cancer and human breast cancer detection where S/S can be evaluated in early, small tumors. Two other instruments appropriate to the animal models will be employed. 2) A flying spot scanner of 1 mm resolution for superficial tumors (mouse only) and adapted to imaging the NIR fluorescence signals. 3) a three-dimensional imager with less than 50 micron resolution requiring snap freezing of the tumor will be used to localize contrast agents in all non-human tumors. The latter system is essential to a critical evaluation of the phased array system. Seven NIR contrast agents based upon ICG and including molecular beacons will be compared in animal models using the above mentioned detection methods. Quantitative comparison will be afforded using the Figure of Merit(M) based upon tumor/tissue contrast agent (C), retention time (R)(min), and fluorescence quantum yield ratio (Q). M is calculated on the basis of a linear model (i.e., the product of these three quantities). Thus, an intensive, ambitious quantitative evaluation of currently available contrast agents will afford an animal model data base transfer to human breast tumors using FDA approved ICG (and others later) and phased array localization co-registered with gadolinium chelate tumor MRI images in "bench to bedside" studies (NIH Workshop, September 14-17, 2000).